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In this review paper, the latest literature on the functional properties of phospholipids in relation to inflammation and inflammation-related disorders has been critically appraised and evaluated. The paper is divided into three sections: Section 1 presents an overview of the relationship between structures and biological activities (pro-inflammatory or anti-inflammatory) of several phospholipids with respect to inflammation. Section 2 and Section 3 are dedicated to the structures, functions, compositions and anti-inflammatory properties of dietary phospholipids from animal and marine sources. Most of the dietary phospholipids of animal origin come from meat, egg and dairy products. To date, there is very limited work published on meat phospholipids, undoubtedly due to the negative perception that meat consumption is an unhealthy option because of its putative associations with several chronic diseases. These assumptions are addressed with respect to the phospholipid composition of meat products. Recent research trends indicate that dairy phospholipids possess anti-inflammatory properties, which has led to an increased interest into their molecular structures and reputed health benefits. Finally, the structural composition of phospholipids of marine origin is discussed. Extensive research has been published in relation to ω-3 polyunsaturated fatty acids (PUFAs) and inflammation, however this research has recently come under scrutiny and has proved to be unreliable and controversial in terms of the therapeutic effects of ω-3 PUFA, which are generally in the form of triglycerides and esters. Therefore, this review focuses on recent publications concerning marine phospholipids and their structural composition and related health benefits. Finally, the strong nutritional value of dietary phospholipids are highlighted with respect to marine and animal origin and avenues for future research are discussed.

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL 2 – 4 . Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr −/− background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr −/− mice, Ldlr −/− E06-scFv mice had 57–28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis. A single-chain variable fragment of the antibody E06, which binds to the phosphocholine headgroup of oxidized phospholipids, blocks the uptake of oxidized low-density lipoprotein by macrophages, and reduces inflammation and atherosclerosis in hypercholesterolaemic mice.

Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial. LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705. Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was −0·028 (SD 0·453) in the active group and −0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI −0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of −0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention. The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed. European Commission 7th Framework Programme.

Xkr8–Basigin is a plasma membrane phospholipid scramblase activated by kinases or caspases. We combined cryo-EM and X-ray crystallography to investigate its structure at an overall resolution of 3.8 Å. Its membrane-spanning region carrying 22 charged amino acids adopts a cuboid-like structure stabilized by salt bridges between hydrophilic residues in transmembrane helices. Phosphatidylcholine binding was observed in a hydrophobic cleft on the surface exposed to the outer leaflet of the plasma membrane. Six charged residues placed from top to bottom inside the molecule were essential for scrambling phospholipids in inward and outward directions, apparently providing a pathway for their translocation. A tryptophan residue was present between the head group of phosphatidylcholine and the extracellular end of the path. Its mutation to alanine made the Xkr8–Basigin complex constitutively active, indicating that it plays a vital role in regulating its scramblase activity. The structure of Xkr8–Basigin provides insights into the molecular mechanisms underlying phospholipid scrambling. Cryo-EM and X-ray crystal structures reveal the architecture of the human Xkr8–Basigin complex, providing insights into the molecular mechanism of phospholipid scrambling.

Phospholipid scrambling The plasma membranes of eukaryotic cells have an asymmetrical distribution of phospholipids. Lipid asymmetry can be disrupted during biological processes such as apoptosis, when phosphatidylserine in the inner leaflet of the membrane is exposed on the outer membrane. It has been proposed that activation of a phospholipid scramblase catalyses bidirectional transbilayer movement of phospholipids, and now a protein corresponding to this activity has been identified as TMEM16F, a member of the TMEM16 family of transmembrane proteins. Furthermore, a patient with Scott syndrome, which results from a defect in phospholipid scrambling activity, was found to carry a mutation in the gene encoding TMEM16F. Lipid asymmetry can be disrupted during biological processes such as apoptosis, during which phosphatidylserine in the inner leaflet of the membrane is exposed on the outer membrane. It has been proposed that activation of a phospholipid scramblase catalyses bidirectional transbilayer movement of phospholipids, but the protein corresponding to this activity has not been identified. Here, the protein TMEM16F is identified, and is an essential component for the Ca 2+ -dependent exposure of phosphatidylserine on the plasma membrane. A patient with Scott syndrome, which results from a defect in phospholipid scrambling activity, was found to carry a mutation in the gene encoding TMEM16F. In all animal cells, phospholipids are asymmetrically distributed between the outer and inner leaflets of the plasma membrane 1 . This asymmetrical phospholipid distribution is disrupted in various biological systems. For example, when blood platelets are activated, they expose phosphatidylserine (PtdSer) to trigger the clotting system 2 , 3 . The PtdSer exposure is believed to be mediated by Ca 2+ -dependent phospholipid scramblases that transport phospholipids bidirectionally 1 , 4 , but its molecular mechanism is still unknown. Here we show that TMEM16F (transmembrane protein 16F) is an essential component for the Ca 2+ -dependent exposure of PtdSer on the cell surface. When a mouse B-cell line, Ba/F3, was treated with a Ca 2+ ionophore under low-Ca 2+ conditions, it reversibly exposed PtdSer. Using this property, we established a Ba/F3 subline that strongly exposed PtdSer by repetitive fluorescence-activated cell sorting. A complementary DNA library was constructed from the subline, and a cDNA that caused Ba/F3 to expose PtdSer spontaneously was identified by expression cloning. The cDNA encoded a constitutively active mutant of TMEM16F, a protein with eight transmembrane segments 5 . Wild-type TMEM16F was localized on the plasma membrane and conferred Ca 2+ -dependent scrambling of phospholipids. A patient with Scott syndrome 6 , 7 , which results from a defect in phospholipid scrambling activity 8 , 9 , was found to carry a mutation at a splice-acceptor site of the gene encoding TMEM16F, causing the premature termination of the protein.

Structures of the voltage-gated and phosphatidylinositol 3,5-bisphosphate-activated mouse two-pore channel TPC1 in apo and ligand-bound states provide insights into the selectivity and gating mechanisms of mammalian two-pore channels. Structure of a mouse two-pore ion channel Two-pore channels (TPCs) are organellar voltage-dependent ion channels that are widely expressed in both animals and plants. In mammals, TPC1 and TPC2 regulate the physiological functions of the endolysosomal system. Here, Youxing Jiang and colleagues report the structure of mouse TPC1, a sodium ion (Na + )-selective channel, in both its apo closed state and phospholipid-bound open state by cryo-electron microscopy. Along with functional studies, these data underlie the basis for the difference in selectivity and gating of mammalian TPCs compared to their plant homologues. They also provide information on the mechanisms of activation and regulation by lipid binding. The organellar two-pore channel (TPC) functions as a homodimer, in which each subunit contains two homologous Shaker -like six-transmembrane (6-TM)-domain repeats 1 . TPCs belong to the voltage-gated ion channel superfamily 2 and are ubiquitously expressed in animals and plants 3 , 4 . Mammalian TPC1 and TPC2 are localized at the endolysosomal membrane, and have critical roles in regulating the physiological functions of these acidic organelles 5 , 6 , 7 . Here we present electron cryo-microscopy structures of mouse TPC1 (MmTPC1)—a voltage-dependent, phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P 2 )-activated Na + -selective channel—in both the apo closed state and ligand-bound open state. Combined with functional analysis, these structures provide comprehensive structural insights into the selectivity and gating mechanisms of mammalian TPC channels. The channel has a coin-slot-shaped ion pathway in the filter that defines the selectivity of mammalian TPCs. Only the voltage-sensing domain from the second 6-TM domain confers voltage dependence on MmTPC1. Endolysosome-specific PtdIns(3,5)P 2 binds to the first 6-TM domain and activates the channel under conditions of depolarizing membrane potential. Structural comparisons between the apo and PtdIns(3,5)P 2 -bound structures show the interplay between voltage and ligand in channel activation. These MmTPC1 structures reveal lipid binding and regulation in a 6-TM voltage-gated channel, which is of interest in light of the emerging recognition of the importance of phosphoinositide regulation of ion channels.

Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer) on the cell surface. Using a haploid genetic screen in human cells, we found that ATP11C (adenosine triphosphatase type 11C) and CDC50A (cell division cycle protein 50A) are required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet; that is, they display flippase activity. ATP11C contained caspase recognition sites, and mutations at these sites generated caspase-resistant ATP11C without affecting its flippase activity. Cells expressing caspase-resistant ATP11C did not expose PtdSer during apoptosis and were not engulfed by macrophages, which suggests that inactivation of the flippase activity is required for apoptotic PtdSer exposure. CDC50A-deficient cells displayed PtdSer on their surface and were engulfed by macrophages, indicating that PtdSer is sufficient as an \"eat me\" signal.

Fully targeted mRNA therapeutics necessitate simultaneous organ-specific accumulation and effective translation. Despite some progress, delivery systems are still unable to fully achieve this. Here, we reformulate lipid nanoparticles (LNPs) through adjustments in lipid material structures and compositions to systematically achieve the pulmonary and hepatic (respectively) targeted mRNA distribution and expression. A combinatorial library of degradable-core based ionizable cationic lipids is designed, following by optimisation of LNP compositions. Contrary to current LNP paradigms, our findings demonstrate that cholesterol and phospholipid are dispensable for LNP functionality. Specifically, cholesterol-removal addresses the persistent challenge of preventing nanoparticle accumulation in hepatic tissues. By modulating and simplifying intrinsic LNP components, concurrent mRNA accumulation and translation is achieved in the lung and liver, respectively. This targeting strategy is applicable to existing LNP systems with potential to expand the progress of precise mRNA therapy for diverse diseases. Targeted delivery of mRNA using lipid nanoparticles is currently a challenge. Here, the authors examine the composition of LNPs and report changes to the standard formulation can address issues with liver accumulation and allow for increased tissue specific targeting.